This Phase 2 clinical trial will determine if monthly oral vitamin D can reduce the risk of respiratory complications in children with sickle-cell disease. Accumulating evidence indicates that vitamin D, in addition to its role in calcium and bone homeostasis, is a multifunctional regulator of both innate and adaptive immune responses. Inadequate amounts of vitamin D have been linked to impaired lung function and an increased risk of respiratory infections and asthma. Sickle-cell disease, an orphan disease affecting an estimated 89,000 individuals in the United States, is an inherited red blood cell disorder with acute vaso-occlusive complications and chronic multi-organ damage resulting from microvascular occlusion, hemolysis-induced endothelial dysfunction and vasculopathy. Functional asplenia from sickling-induced infarctions during early childhood impairs immune defenses. Respiratory complications are the leading cause of morbidity and of death in sickle-cell disease. Increased susceptibility to infection and a heightened inflammatory response are critical components of the pathogenesis of lung disease in sickling disorders. Patients with sickle-cell disease are at a high risk for vitamin D deficiency due to limited sun exposure, dark skin color and poor nutrition. Vitamin D has potent antimicrobial and immunomodulatory properties that may help prevent respiratory complications in sickle-cell disease. This project is a 2-year controlled, double-blind, randomized Phase 2 clinical trial comparing the efficacy of oral vitamin D3, 100,000 IU (2.5 mg) given once a month, with standard-dose oral vitamin D3, 12,000 IU (0.3 mg) given once a month, in reducing the rate of respiratory events in 80 children and adolescents, 3 to 20 years old, with sickle-cell disease. This trial has three specific aims: (1) to determine whether monthly oral vitamin D3 (100,000 IU [2.5 mg]), given to children and adolescents with sickle-cell disease, will reduce the rate of respiratory events, defined as respiratory infections, exacerbations of asthma, and episodes of the acute chest syndrome;(2) to evaluate the effects of monthly oral vitamin D3 on pulmonary function, airway hyperreactivity and airway inflammation;and (3) to examine the effects of monthly oral vitamin D3 on immune function, using measures of T-cell effector and regulatory function and of systemic inflammation.